Extension of a predictive substrate model for human cytochrome P4502D6.

1. Metoprolol, indoramine, codeine, tamoxifen and prodipine, compounds which are clinically used, and MDMA (ecstasy) were fitted in a small molecule model for substrates of human cytochrome P4502D6. 2. For both the R- and S-enantiomer of metoprolol, the R- and S-enantiomer of MDMA, and for indoramine and codeine (all proven substrates of cytochrome P4502D6) an acceptable fit in the substrate model was obtained. 3. For tamoxifen, for which the involvement of cytochrome P4502D6 in the 4-hydroxylation is uncertain, no acceptable fit could be obtained in the substrate model. 4. For prodipine, a competitive inhibitor of P4502D6, for which the involvement of P4502D6 in the metabolism is uncertain, no acceptable fit in the substrate model could be obtained. 5. The substrate model was extended in a direction in which two large known substrates extend from the original substrate model. This extension did not change the flat hydrophobic region of the original substrate model.